Detecting cancer's family ties

Researcher Amanda Paulovich believes study of inherited defects in DNA repair could yield new tools for early cancer detection

Feb. 19, 2004

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By BARBARA BERG

Dr. Heidi Zhang and Richard Ivey at work in the lab of Dr. Amanda Paulovich, who leads a project to create tests to identify healthy women at high risk of developing breast cancer later in life. The tests examine the blood for molecules called biomarkers that provide disease susceptibility information.

Photo by Todd McNaught

Conventional wisdom has long held that cancers are either hereditary or due to chance events. A small percentage of cancer patients have a strong family history of the disease, while the majority of those who develop the disease have no obvious reason for their fate.

Dr. Amanda Paulovich, a geneticist and oncologist, challenges this distinction. In her view, all cancers are traceable in part to the genes we inherit. The confusion in the field has arisen because most hereditary factors have defied discovery using available methods.

"All cancers have a genetic component," said Paulovich, who joined the Clinical Research Division last fall. "It's just that only about 5 percent of all cancers result from defects in single genes-and those are the easiest ones to find. If multiple genes are in-volved, or if the defects are subtle, there aren't straight-forward experiments available to identify them."

With the recent explosion of new techniques applicable to cancer research, Paulovich expects answers are now within reach. In her laboratory in the Hutchinson Building, she is working to develop simple tests that can identify healthy women who are likely to develop breast cancer later in life. The tests examine the blood for biomarkers, molecules that provide information about disease risk, type, stage and response to treatment. She and others in the field reason that many lives could be saved using such tests if individuals identified to be at high risk for cancer undergo regular surveillance to check for the onset of cancer at an early stage, when it is easier to cure.

Paulovich felt drawn to this research focus while a medical resident in Boston several years ago. Like many of her colleagues, she was struck by the obvious reason behind why some cancer is readily curable in particular patients and not in others. The disparity was based on whether a patient's cancer was diagnosed before it had spread beyond the original location of the tumor.

"If a cancer is localized, we can cure it virtually 100 percent of the time with surgery," she said. "Once it has spread, it requires chemotherapy and becomes much harder to treat successfully."

Eager to find a way to improve the survival odds for all cancer patients, Paulovich weighed her research options. She considered whether to try to develop better drugs for treating advanced cancer or to investigate ways to improve cancer diagnosis. She opted for the latter approach once she realized some of the challenges unique to cancer drug development, she said.

"The average size of a tumor is about a billion cells," Paulovich said. "Even if a drug can reach and kill 99 percent of the tumor-which many would consider to be a good drug-you're still left with 10 million cancer cells, each of which can continue to multiply.

"In addition, not all cancer cells in a tumor are identical-they frequently contain different mutations. So some cells are inherently resistant to the drug."

Another problem, she said, is that most chemotherapy drugs in use today are toxic to both normal and healthy cells. Although scientists are now trying to find drug targets that are unique to cancer cells-thus sparing healthy cells from damage-the research is still at an early stage.

"You need incredible specificity to target a drug only to cancer cells. Right now, Gleevec is one of a few examples of drugs that can do this," she said, referring to an anticancer agent that works effectively against leukemia and some intestinal tumors while causing minimal side effects. Although Gleevec is not a proven cure for cancer, many patients remain free of the disease while taking the drug. Other researchers, including those at the center, have also had success using antibodies to target drugs to cancer cells.

Paulovich ultimately decided to pursue research that might yield new diagnostic tools for early cancer detection. As a step toward achieving this goal, her current work is aimed at developing a reliable test that can pick out women who are most likely to develop breast cancer because they have inherited genes that put them at higher risk than women in the general population. Such women would be good candidates to receive more intensive cancer screening.

Leadership position

Her background positions her well for success in these studies. In addition to receiving a medical degree from the University of Washington, Paulovich also earned a doctorate in genetics. Her thesis focused on the genes that control the repair of DNA damage in yeast, a single-cell organism that has led to much insight in cancer biology. She completed her residency and an oncology fellowship at Massachusetts General Hospital and Dana Farber Cancer Institute in Boston while also working at the Massachusetts Institute of Technology/Whitehead Institute Center for Genomics Research.

"We are very fortunate to be able to recruit an individual to provide leadership on our biomarker discovery project with the training that she has had in basic science, clinical science and genomics," said Dr. Lee Hartwell, center president and director. "Mandy has hit the road running with great energy and is generating an enormous amount of interest and activity in biomarker discovery."

Breast-cancer risk

Paulovich and others who believe that all or most cancers can be traced in part to our inherited genetic blueprint base their arguments on numerous studies led by researchers who explore the connection between genes and the onset of disease. She has chosen to focus on identifying subtle inherited factors that influence breast-cancer risk because of a striking convergence of evidence that links the risk with defects in an individual's ability to repair damaged DNA.

"Five of the six genes that are known to cause hereditary forms of breast cancer are part of a cellular pathway to repair DNA breaks," she said. "In addition, there is compelling evidence that defects in DNA repair may play a factor in many cases of so-called non-hereditary, or sporadic, breast cancer."

That evidence stems from work led by Dr. David Scott, a former researcher at the Paterson Institute for Cancer Research in Manchester, England. Scott collected blood samples from many breast-cancer patients who had no obvious family history of the disease. He then exposed the samples to radiation, which causes breaks in DNA, and examined whether the cells in each sample were able to repair the damage. The experiments revealed that blood cells from breast-cancer patients were less likely to be able to repair DNA damage than cells from women in the general population.

What's more, Scott found that cells from the cancer patients' relatives-even if they were healthy-were also poor DNA-damage repairers.

"This shows that the inability to repair DNA damage is an inherited trait," Paulovich said.

The penetrance factor

Scientists say that inherited traits that lead to a very high risk of cancer have high penetrance, meaning that the genetic defect is potent enough to trigger cancer in a large percentage of people with that genetic makeup. Less penetrant traits-which might be only slightly defective single genes or a subtle combination of several weakly mutant genes-cause cancer in a small percentage of those who inherit them, making them difficult for scientists to pinpoint. Paulovich said that so-called "sporadic" cases of cancer-those not associated with strong family history-are in fact inherited cancers that result at least in part from genetic traits of very low penetrance.

Finding the genes responsible for the low-penetrance inability to repair DNA would be a near impossible task. Instead, Paulovich is taking a different tactic that involves testing the functioning of the whole DNA-repair pathway. The approach relies on a relatively new field of study called proteomics, in which researchers simultaneously analyze many?or all of the proteins produced by a cell.

Proteins-the molecules that build all of an organism's working parts-are made from instructions buried in the DNA code of genes. Protein analysis gives researchers a functional readout of whether a gene is working properly.

Tailored therapy

Currently, Paulovich, along with her lab technicians Richard Ivey and Brian Piening, and Dr. Heidi Zhang, a staff scientist in the Early Detection and Intervention Initiative, are working to improve the available technology for protein analysis in order to develop a reliable test for monitoring the DNA-repair pathway in human blood samples.

"The basic question we want to ask is, 'are common breast cancers due to this inherited deficiency in DNA repair?'" she said.

The research could also lead to better ways to tailor radiation therapy to individual patients.

"This kind of test could help us determine which patients are very sensitive to X-rays," she said. "Patients who are less sensitive could receive higher doses, which would be more effective against their cancer and less toxic overall."

Cautious enthusiasm

Citing a survey published earlier this year in the Journal of the American Medical Association, Paulovich said that the public is enthusiastic about opportunities to be screened for the early onset of cancer. But as the scientific and medical communities conduct research to develop new early cancer detection tests, she cautioned that they must be wary of the premature release of tests that diagnose cancers that do not warrant treatment. For example, many researchers believe that the PSA test for prostate cancer identifies numerous cancers that would never become aggressive or cause harm, which leads many men to choose unnecessary treatments with often serious side effects.

"We are all eager to develop new tests for cancer diagnosis," she said. "But it's our moral responsibility to see that those tests can distinguish cancers that warrant medical intervention from those that do not."